Highlights from Recent Cancer Literature
Journal: Cancer Research (2016)

Dolma and colleagues hypothesized that the similarity between glioblastoma stem cells and normal neural stem cells would predict that neuroactive compounds may be active against glioblastoma stem cells. The authors screened 680 neuroactive compounds against three glioblastoma stem cell lines, two normal neural stem cell lines, and a fibroblast control. Their most active compounds converged on modulators of dopaminergic (27%), cholinergic (17%), adrenergic (18%), and serotonergic (9%) pathways. They confirm several dopamine receptor D4 (DRD4) antagonists showed activity against fresh patient-derived glioblastoma cells and validated this in vivo, showing synergy with temozolomide. The mechanism of DRD4 inhibition was tied to inhibition of the autophagy-lysosomal degradation pathway. This study proposes a rational, novel therapeutic agent in the treatment of glioblastoma and expands our knowledge base of the biology and neurochemical properties of glioblastoma.Dolma S, Selvadurai HJ, Lan X, Lee L, Kushida M, Voisin V, et al. Inhibition of dopamine receptor D4 impedes autophagic flux, proliferation, and survival of glioblastoma stem cells. Cancer Cell 2016;29:859–73.Lu and colleagues demonstrate that BRAFV600E expression facilitates invasion by promoting the formation of F-actin and cortactin-positive invadopodia-like structures, detected at higher density in melanoma biopsies of patients with BRAFV600E compared with tumors with BRAFWT. Cortactin-positive foci were also elevated in a BRAFV600E-driven murine melanoma model, and treatment of human and murine tumors with BRAF inhibitor vemurafenib decreased cortactin foci significantly. Mechanistically, BRAFV600E inhibition downregulated several genes associated with invadopodia formation. In addition, BRAFV600E triggered ERK-induced phosphorylation of cortactin, driving the F-actin rich structure formation and phosphorylation of exocyst subunit EXO70 (EXOC7), increasing secretion of matrix-degrading matrix metalloproteinases to the invasive foci. Thus, BRAFV600E is not only a melanoma driver oncogene but also triggers invasion, suggesting BRAFV600E inhibition as a strategy to prevent melanoma progression.Lu H, Liu S, Zhang G, Kwong LN, Zhu Y, Miller JP, et al. Oncogenic BRAF-mediated melanoma cell invasion. Cell Rep 2016;15:2012–24.The αβ or γδ T-cell receptor (TCR) heterodimer originates from somatic rearrangement, with the most variable region, CDR3, having a critical role in antigen recognition. Characterizing the repertoire of tumor-infiltrating T-cells (TIL) could identify mutated proteins or neoantigens expressed by tumor-reactive T-cell clones, with applications towards immunotherapy. Li and colleagues developed a computational “CDR3 assembly” method, validated using immunoSEQ. They analyzed ∼9,000 samples covering 29 different cancers from The Cancer Genome Atlas. TILs generally utilized a similar CDR3 distribution to that found from T-cells in peripheral blood from healthy donors. Also, T-cell diversity correlated strongly with the load of nonsynonymous somatic mutations. Finally, this method nominated SPAG5 and TSSK6 as immunogenic cancer antigens and, paired with exome sequencing, predicted a neoantigen from the PRAMEF4 gene. This computational “CDR3 assembly” method may help in the development of cancer vaccines, adoptive T-cell, and chimeric antigen receptor T-cell therapies.Li B, Li T, Pignon JC, Wang B, Wang J, Shukla SA, et al. Landscape of tumor-infiltrating T cell repertoire of human cancers. Nat Genet 2016;48:725–32.SOX4, a developmental transcription factor, aids metastatic progression, however, the direct target genes of SOX4 that mediate cancer progression are unknown. Lee and colleagues identified transmembrane protein 2 (TMEM2) as a downstream target of SOX4. Silencing of SOX4 decreased TMEM2, while overexpressing SOX4 increased TMEM2 transcript levels in breast cancer cells. Using ChIP-qPCR, the authors determined that SOX4 could bind the TMEM2 promoter, increasing the expression of TMEM2. Silencing of TMEM2 in SOX4-overexpressing cells reduced invasion and migration. Overexpressing TMEM2 in breast cancer cells increased, and silencing decreased invasion and migration capacity. Silencing of TMEM2 in vivo reduced and overexpression increased lung metastases in a preclinical animal model. Thus, the authors have identified TMEM2 as a direct transcriptional target of SOX4 that aids in breast cancer metastasis.Lee H, Goodarzi H, Tavazoie SF, Alarcón CR. TMEM2 is a SOX4 regulated gene that mediates metastatic migration and invasion in breast cancer. Cancer Research; Published OnlineFirst June 21, 2016; doi:10.1158/0008-5472.CAN-15-2322.Although nanoparticles promise improved drug delivery with reduced side effects, nanoparticles ineffectively target disseminated disease, the major cause of death in cancer. Shamay and colleagues identified P-selectin expression across human malignancies, including stroma. They prepared targeted nanoparticles containing fucoidan, which displays nanomolar affinity to P-selectin, and found robust and specific binding to P-selectin. Coadministration of the fucoidin containing nanoparticles with ionizing radiation (to induce expression of P-selectin to the membrane) drove durable tumor regression in vivo. Strikingly, distant metastases also regressed across two in vivo metastatic models. As proof of principle, the authors then encapsulated a MEK inhibitor in fucoidan-based nanoparticles, selectively administering high doses of drug in vivo without systemic toxicity. This new strategy promises precise targeting of disseminated disease in a variety of malignancies.Shamay Y, Elkabets M, Li H, Shah J, Brook S, Wang F, et al. P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Sci Transl Med 2016;8:345ra87.Dual targeting of CTLA-4 and PD-1 has improved survival for patients with melanoma. Predicting the efficacy of treatment and optimal design of combination therapy requires understanding how immune checkpoint inhibitors with complementary mechanisms affect the tumor milieu. In a randomized phase 2 study, Weber and colleagues allocated patients to receive nivolumab followed by ipilimumab or the reverse sequence (70 evaluable patients per arm). Administration of nivolumab followed by a planned switch to ipilimumab improved clinical outcomes (12-month overall survival 76% versus 54%), with more frequent treatment-related grade 3-4 adverse events. Important limitations of this trial include limited power to detect differences in outcome and imbalances in baseline characteristics between treatment groups. Nevertheless, these compelling results should prompt further elucidation of mechanisms that account for improved efficacy, to optimize combinatorial treatment regimens.Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, et al. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomized, phase 2 trial. Lancet Oncol 2016;17:943–55.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.